Acute myocardial infarction (AMI) affects over 1 million US individuals a year and at present there are no preventative therapeutics other than direct percutaneous coronary intervention. DecImmune's long-term goal is to develop therapeutics to reduce the severe lethal reperfusion injury that follows removal of coronary artery blockage. This goal is based on our identification of a novel pathway that is activated by reperfusion of ischemic tissues and development of a peptide mimetope (N2) and monoclonal antibodies that block inflammation. The current proposal is a resubmission of an application that follows from our completion of the milestones of an earlier Phase I grant. The revised application addresses the concerns of the reviewers and includes substantial new results such as a more detailed and complete protocol and an increased number of pigs to enhance statistical power. Our earlier studies demonstrated that the novel pathway we identified in rodents is conserved in humans. Therefore, in order to move the potential therapeutics to clinical trials, we propose to extend our observations in a pig model. Given the high degree of physiological similarities with the human vascular system, pigs represent a good animal model. Successful achievement of the goals of the Phase II application will lead to testing of the therapeutics in Phase I clinical trials. PUBLIC HEALTH RELEVANCE: There are over 1.2 million heart attacks annually in the US. In spite of advances made in thrombolytic therapy and angioplasty, up to 25% of men and 38% of women die within one year following a heart attack. A significant factor in the high morbidity and mortality is due to the damage that is caused to the cardiac tissues by acute inflammation at the site of ischemia and reperfusion. The goal of this project is to develop a therapeutic compound that will inhibit the acute inflammation that occurs at the site of ischemia in patients following a myocardial infarction, minimizing the amount of microvascular damage and protecting viable cardiac cells in the infarct zone. Studies described in the application will extend our testing of the inhibitors to a swine model of acute myocardial infarction.